Poly(ADP-ribose) polymerase 1 (PARP1) is a multi-domain protein containing a catalytic and other domains, some of which are involved in DNA binding and interaction with other molecules. It catalyzes the formation of poly-ADP-ribose (PAR) polymers by transferring multiple ADP-ribose units from NAD+ onto acceptor proteins, a post-translational modification termed PARylation. PARP1 is cleaved during apoptosis, but is not essential for cell death as mice expressing uncleavable PARP1 develop normally as do mice lacking this protein. We find that knock-in mice globally expressing a non-cleavable PARP1 mutant (constitutively active mutant) exhibit a high bone mass phenotype owing to decreased OC differentiation and bone resorption, while bone formation is unaffected. Conversely, germline ablation of Parp1 in mice causes osteopenia stemming from increased osteoclastogenesis, while osteogenesis is unaltered. Thus, PARP1 gain-of-function mutation hinders osteoclastogenesis whereas loss-of-function promotes this process. Mechanistically, we find that PARP1 is highly expressed by OC precursors and it is degraded during OC differentiation, and that the master OC transcription factor, NFATc1, is PARylated during osteoclastogenesis, implying post-translational regulation by PARP1. We also find that PARP1 inhibits the expression of the global repressor of OC suppressors, Blimp1. Intriguingly, while an inhibitor of PARP1 enzymatic activity enhances OC formation from mouse bone marrow macrophages cultured in the presence of M-CSF and RANKL, in vitro expression of a PARP1 mutant lacking the catalytic domain inhibits osteoclastogenesis. These observations suggest that PARP1 inhibits OC differentiation via both PARylation and other mechanisms not requiring its catalytic activity. However, the relative roles of PARP1 complex regulatory effects on osteoclastogenesis are unknown. The central hypothesis of this proposal is that PARP1 inhibits bone resorption via PARylation -dependent and - independent antagonism of osteoclastogenesis. We will test this hypothesis in the following two aims. Aim 1: Determine the skeletal actions of PARP1. Aim 2: Define the mechanisms of PARP1 regulation of osteoclastogenesis. The proposed work will determine PARP1 physiologic importance in modulating bone homeostasis, and its mechanism of action. Therefore, this proposal will break new ground on bone remodeling, focusing on a new player in OC regulation. Understanding PARP1 role in bone remodeling will clarify unrecognized, potential side effects of a new class of drugs and define a possible new avenue of research for therapeutic development with the purpose of inhibiting bone resorption.